Is AMZ1 p.Val227Ala (c.680T>C) pathogenic?

AMZ1 p.Val227Ala (c.680T>C) is classified Likely benign in AMZ1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-15). AlphaMissense: likely benign (0.0611); Rare (popmax 0.409%, nfe).

How common is AMZ1 p.Val227Ala (c.680T>C) in the general population?

AMZ1 p.Val227Ala (c.680T>C) is rare (popmax 0.409%, nfe) (gnomAD).

What do computational predictors say about AMZ1 p.Val227Ala (c.680T>C)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

AMZ1 p.Val227Ala

c.680T>C · rs150799683 · VCV724990

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.409%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.002	strongly benign-leaning
SaProt	LLR -4.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.6	GERP -2.7
Regional constraint	o/e 1.53	unconstrained · MANE · 12 kb · p 2.2e-43 · regional, not allelic
Overall
CADD	0.007	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.409% European (non-Finnish) · 4,772/1,166,092 alleles

Filtering AF 0.399% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.395%

Overall 0.316% 5,008/1,583,036 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.409%	244
Remaining individualsnot grpmax-eligible	0.21%	476
Middle Eastern	0.0681%	1,468
Admixed American	0.0551%	1,815
Ashkenazi Jewishnot grpmax-eligible	0.0464%	2,156
African / African-American	0.0448%	2,230
Finnishnot grpmax-eligible	0.0435%	2,300
South Asian	0.00115%	87,168

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AMZ1
Protein: p.Val227Ala
Coding: c.680T>C
MANE Select: NM_001384743
dbSNP: rs150799683
Type: single nucleotide variant
Location: chr7:2709153 (GRCh38)
Gene constraint: LOEUF 1.88 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.62

Full AMZ1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMZ1 p.Arg481Ter Likely benign ★★ same type
AMZ1 p.Pro394Leu Likely benign ★★ same type
AMZ1 p.Ala122Pro Uncertain significance ★ ⚠ same type
AMZ1 p.Ala172Val Uncertain significance ★ ⚠ same type
AMZ1 p.Ala188Asp Uncertain significance ★ ⚠ same type
AMZ1 p.Ala208Ser Uncertain significance ★ ⚠ same type
AMZ1 p.Ala208Thr Uncertain significance ★ ⚠ same type
AMZ1 p.Ala230Val Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/amz1-p-val227ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown